Two-Chain Mature Hepatocyte Growth Factor-Specific Positron Emission Tomography Imaging in Tumors Using 64Cu-Labeled HiP-8, a Nonstandard Macrocyclic Peptide Probe
Two-Chain Mature Hepatocyte Growth Factor-Specific Positron Emission Tomography Imaging in Tumors Using 64Cu-Labeled HiP-8, a Nonstandard Macrocyclic Peptide Probe
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DOI：
10.1021/acs.molpharmaceut.2c01020
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发表时间：
2023-03-02
影响因子：
4.9
通讯作者：
Mukai，Hidefumi
中科院分区：
文献类型：
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作者：
Warashina，Shota;Sato，Hiroki;Mukai，Hidefumi
双链肝细胞生长因子（tcHGF）是HGF的成熟形式，与恶性肿瘤和抗癌药物耐药性有关;因此，其定量是癌症诊断的重要指标。在肿瘤中，活化的tcHGF几乎不排放到体循环中，表明tcHGF是使用正电子发射断层扫描（PET）进行分子成像的极好靶点。我们最近发现了HGF抑制肽-8（HiP-8），其以纳摩尔亲和力特异性结合人tcHGF。本研究采用交联环拉胺（cyclam）螯合剂CB-TE 1 K1 P合成了64 Cu标记的HiP-8分子，并将其应用于人HGF基因敲入的人源化小鼠。基于放射性高效液相色谱的代谢稳定性分析表明，超过90%的探针存在于血液中的完整形式至少为15分钟。在PET研究中，显着选择性可视化的hHGF过表达肿瘤与hHGF阴性肿瘤中观察到双荷瘤小鼠。通过竞争性抑制，标记的HiP-8在hHGF过表达肿瘤中的积累显著减少。此外，磷酸化MET/HGF受体的放射性和分布在组织中共定位。这些结果表明，64 Cu标记的HiP-8探针适用于体内tcHGF成像，并且分泌蛋白如tcHGF可以作为PET成像的靶点。
Two-chain hepatocyte growth factor (tcHGF), the mature form of HGF, is associated with malignancy and anticancer drug resistance; therefore, its quantification is an important indicator for cancer diagnosis. In tumors, activated tcHGF hardly discharges into the systemic circulation, indicating that tcHGF is an excellent target for molecular imaging using positron emission tomography (PET). We recently discovered HGF-inhibitory peptide-8 (HiP-8) that binds specifically to human tcHGF with nanomolar affinity. The purpose of this study was to investigate the usefulness of HiP-8-based PET probes in humanHGFknock-in humanized mice.64Cu-labeled HiP-8 molecules were synthesized using a cross-bridged cyclam chelator, CB-TE1K1P. Radio-high-performance liquid chromatography-based metabolic stability analyses showed that more than 90% of the probes existed in intact form in blood at least for 15 min. In PET studies, significantly selective visualization of hHGF-overexpressing tumors versus hHGF-negative tumors was observed in double-tumor-bearing mice. The accumulation of labeled HiP-8 into the hHGF-overexpressing tumors was significantly reduced by competitive inhibition. In addition, the radioactivity and distribution of phosphorylated MET/HGF receptor were colocalized in tissues. These results demonstrate that the64Cu-labeled HiP-8 probes are suitable for tcHGF imaging in vivo, and secretory proteins like tcHGF can be a target for PET imaging.